Benzothiadiazole compounds for treating hypertension

ABSTRACT

Compounds of the formula   &lt;IMAGE&gt;   and their pharmaceutically acceptable salts, wherein the substituents are as defined herein, having antihypertensive activity.

This application is a division of our prior copending application Ser.No. 584,576, filed Feb. 29, 1984 now U.S. Pat. No. 4,576,941.

BACKGROUND OF THE INVENTION

This application relates to compounds, their pharmaceutically acceptablesalts, and pharmaceutical preparations made therefrom, having utility inthe treatment of hypertension in subjects suffering therefrom.

SUMMARY OF THE INVENTION

Broadly stated, the present invention comprises compounds of the formula##STR2## and pharmaceutically acceptable alkali metal, alkaline earthmetal, and acid addition salts thereof, wherein

X is hydrogen or ##STR3## wherein A is alkyl, phenyl, or phenylsubstituted with up to 3 substituents selected from the group consistingof halo, alkyl having up to 7 carbon atoms, --CF₃, OH, COOH, NH₂, andSO₂ NH₂ ;

m is 0 to 3 inclusive;

Y is --OR or --N(R)R;

R₁, R₂, R₃ and R₄ are independently R or amino-alkyl,

Z₁, reading toward the M₁ substituent, is selected from the groupconsisting of --(CH₂)_(n) --, --N(R)CH₂ (CH₂)_(n) --, --N(R)CH₂(CH₂)_(n) NH--, --(CH₂)_(n) SO₂ --, --(CH₂)_(n) N(R)SO₂ --, --(CH₂)_(n)--N(R)--, --(CH₂)_(n) N(R)C(O)--, --(CH₂)_(n) C(O)N(R)--, or --(CH₂)_(n)C(O)--, in which n is 0 to 6 inclusive, and one of the (CH₂) groups canbe mono- or disubstituted with methyl or ethyl;

M₁ is independently selected from the group consisting of aryl, fusedpolycyclic aryl, heteroaryl, fused heterocyclic-aryl, and fusedcycloalkylaryl, wherein up to 3 carbon atoms of M₁ can be oxidized to--C(O)-- or replaced by --N(R)--, --O--, --S--, or --SO₂ --; wherein M₁has two or three substituents selected from the group consisting ofhalogen, alkyl, aminoalkyl, aralkyl, cycloalkyl, alkylamino, acylamino,acylaminoalkyl, acylaminoalkylamino, trifluoromethyl, nitro, cyano,--OR, --SR, --C(O)OR, --S(O)R, --SO₂ R, --C(O)N(R)R, --N(R)R, or --SO₂N(R)R;

wherein in each occurrence R is independently hydrogen, alkyl,cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaralkyl, or heteroaryl;

wherein the alkyl groups and the alkyl moieties contain up to 7 carbonatoms, the cycloalkyl and heterocyclic groups and moieties are saturatedor unsaturated and contain 3 to 12 atoms, and the aryl and heteroarylrings contain up to 12 atoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Preferred compounds of the present invention include those of thegeneral formula given above in which Y is hydroxy, benzyloxy, or loweralkoxy; R₁, R₂, R₃ and R₄ are each hydrogen, alkyl, aryl, aralkyl,cycloalkyl, or w-amino ("omega-amino")alkyl wherein the amino isunsubstituted or mono- or disubstituted with alkyl, aryl, or aralkyl, oris incorporated in a saturated or unsaturated one- or two-ringheterocyclic moiety containing preferably up to 12 atoms in the ring; mis 1 or 2; and A is lower alkyl, lower cycloalkyl, or phenyl. Morepreferably, R₂ and R₄ are hydrogen; and R₁ and R₃ are each hydrogen orlower alkyl.

The alkyl groups per se and the alkyl moieties in alkoxy, aralkyl,cycloalkyl, aminoalkyl, and the like, may be straight-chained orbranched and preferably contain from 1 to 7 carbon atoms. Such groupsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary-butyl, amyl, iso-amyl, hexyl, and the like. Preferably thealkyl groups are lower alkyl, which term shall refer to alkyl groupscontaining from 1 to 4 carbon atoms, straight-chained or branched. Thepreferred substituents for lower alkyl include amino, --OH, --CONH₂,--OR, and --SR. The cycloalkyl groups and moieties are saturated orunsaturated and contain 3 to 12 carbon atoms and preferably 3 to 9carbon atoms.

Preferred structures for Z₁ include a chemical bond and an alkylenebridge --(CH₂)_(n) -- in which n is 0, 1, 2, 3, or 4.

Preferred cyclic and polycyclic ring structures contain up to 20 carbonatoms and include such radicals as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, norbornyl, phenyl, tolyl, benzyl,phenethyl, indolyl, indolinyl, hydroxybenzyl, indanyl, naphthyl,tetrahydronaphthyl, decanhydronaphthyl, pyridyl, quinolyl, isoquinolyl,guanidino, pyrrolidyl, pyrrolyl, morpholinyl, furyl, furfuryl,tetrahydrofurfuryl, benzimidazolyl, thienyl, imidazolyl,tetrahydroisoquinolyl, and the like, specifically including all isomersof radicals named herein that have more than one isomer.

M₁ is phenyl, fused aryl-cycloalkyl, or fused polycyclic aryl in whichthe aryl group or moiety carries two or three substituents other thanhydrogen. One, two or three of the carbon atoms anywhere in M₁ can be--C(O)--, or replaced by --SO₂, --N(R)--, --O--, or --S--. Preferredstructures include phenyl, indanyl, ##STR4## and benzimidazolyl.Preferred substituents for the aryl ring include halogen, nitro, loweralkyl, --COOH, carboxy-lower alkoxy, phenoxy, and hydroxy; sulfamoylwhich is optionally substituted with alkyl; and amino which isoptionally substituted with lower alkyl, phenyl, phenyl-lower alkyl,heteroaryl-lower alkyl, nitro-lower alkyl, lower alkyl-carbonyl, andlower alkyl-carbonyl-amino-alkyl, (e.g., CH₃ C(O)NH(CH₂)₂₋₄ NH--, CH₃C(O)NH--, and furfurylamino). The M₁ group is preferably connected tothe main chain by non-labile bonds, so that the molecule (1) resistscleavage in the stomach and is thus intact when it enters the blood,which enhances the therapeutic effect and duration of the compound andmay reduce undesirable side-effects.

The halo groups include fluoro, chloro, bromo and iodo. Preferred heteroatoms are S, O, and N. Preferred acyl groups are lower alkyl-carbonyl,and benzoyl.

Compounds in accordance with the present invention are readily preparedemploying known starting materials and procedures. It will be understoodby those skilled in the art that the carbon atoms denoted as C* informula (1) can be asymmetric centers, such that the inventive compoundsmay exist in (R,R), (R,S), (S,R), and (S,S) forms. Individual isomersand diastereo-isomeric mixtures of said forms are within the scope ofthe invention. The preferred forms have the (S) or (S,S) configuration.

The compounds of the formula (1) can be prepared by reacting a compoundof the formula (2): ##STR5## with compound (3): ##STR6## wherein thesubstituents are as defined hereinabove. The reaction can be carried outby converting compound (2) to the acid chloride by reaction with oxalylchloride, and then adding compound (3). Alternatively, compounds (2) and(3) can be condensed directly, in the presence of a suitable couplingagent such as DCC (dicyclohexylcarbodiimide) or CDI(N,N'-carbonyldiimidazole) in a reaction familiar to those of ordinaryskill in the peptide synthesis art. Condensation is preferred where X ishydrogen. For other X substituents, proceeding via a coupling agent ispreferred where the reaction can proceed with a yield higher than thatprovided by the corresponding acid chloride route. The thermal ##STR7##group can, if desired, be converted to hydrogen by hydrolysis with amild acid. The above reactions proceed in a straightforward manner in asuitable solvent at temperatures ranging from 0° C. to 150° C.

The reaction products are sometimes obtained as a mixture ofdiastereoisomers which can be separated by standard methods offractional crystallization or chromatography.

The compounds of this invention form salts, which are also within thescope of the invention, with various inorganic and organic acids andwith alkali metals and alkaline earth metals such as potassium andcalcium. The pharmaceutically-acceptable acid addition salts of thecompounds of the present invention may be prepared by conventionalreactions by reacting the free amino acid or amino ester with anappropriate acid providing the desired anion, either in a solvent ormedium in which the salt is insoluble, or in water and removing thewater by freeze-drying. The salts of strong acids are preferred. Asexemplary, but not limiting, of pharmaceutically-acceptable acid saltsare the salts of hydrochloric, hydrobromic, sulfuric, nitric, acetic,fumaric, malic, maleic and citric acids.

The action of the enzyme renin on angiotensinogen, a pseudoglobulin inblood plasma, produces the decapeptide angiotensin I. Angiotensin I isconverted by angiotensin converting enzyme (ACE) to the octapeptideangiotensin II. The latter is an active pressor substance which has beenimplicated as the causative agent in various forms of hypertension invarious mammalian species, e.g., rats and dogs. The compounds within thescope of this invention which intervene in the renin-to-angiotensinI-to-angiotensin II sequence inhibit angiotensin I converting enzyme andtherefore are useful in reducing or relieving hypertension. Furthermore,the compounds within the scope of the present invention which possessdiuretic activity promote relief from hypertension by promotingdiuresis, and consequently have utility in treating congestive heartfailure. Compounds within the scope of the present invention can alsosimultaneously possess ACE inhibitory and diuretic activity, which isparticularly unexpected in view of the fact that such simultaneousactivity cannot be predicted from prior art compounds. Thus by theadministration of a composition containing one or a combination ofcompounds of formula (1) or pharmaceutically-acceptable salts thereof,hypertension in the species of mammal suffering therefrom is alleviated.A single dose, or preferably two to four divided daily doses, providedon a basis of about 0.1 to 100 mg per kilogram per day, preferably about1 to 50 mg per kilogram per day, is appropriate to reduce bloodpressure. The substance is preferably administered orally, but aparenteral route such as subcutaneously, intramuscularly, intravenouslyor intraperitonealy can also be employed.

The compounds of the invention can be utilized to achieve the reductionof blood pressure by formulating one or more of them in compositionssuch as tablets, capsules or elixirs fo oral administration or insterile solutions or suspensions for parenteral administration. About 10to 500 mg of a compound or mixture of compounds of formula (1) orphysiologically acceptable salt(s) thereof is compounded with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein these compositions or preparations is such that a suitable dosage inthe range indicated is obtained.

Illustrative of the adjuvants which may be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid and the like; a lubricant such as magnesiumstearate; a sweetening agent such as sucrose, lactose or saccharin; aflavoring agent such as peppermint, oil of wintergreen or cherry. Whenthe dosage unit form is a capsule, it may contain in addition tomaterials of the above type a liquid carrier such as a fatty oil.Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection, a naturallyoccurring vegetable oil like sesame oil, coconut oil, peanut oil,cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate,and the like. Buffers, preservatives, antioxidants and the like can beincorporated as required.

Specific embodiments of the invention are illustrated in the followingExamples.

EXAMPLE I

To a mixture containing 100.0 gm (0.751 mol) of aminoacetaldehydediethyl acetal and 101.7 gm (1.01 mol) of triethylamine in 250 ml oftetrahydrofuran at 0° C. and under an atmosphere of nitrogen was addeddropwise over a 25 minute period 137.4 gm (0.823 mol) of ethylbromoacetate. The ice bath was removed and the reaction mixture stirredat room temperature. After 19 hours the mixture was filtered andconcentrated in vacuo. The residue was taken up in ether and washedtwice with water and once with brine. It was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed via HPLC [Water's 500, 50% ether in hexanes, k'=2.0] togive 56.0 gm (34%) of compound (I-A), ethylN-(2,2-diethoxyethyl)glycinate, as an oil.

A mixture of 55.8 gm (0.254 mol) of ethylN-(2,2-diethoxyethyl)glycinate, 50.7 gm (0.177 mol) of1-amino-3-chloro-4,6-benzenedisulfonamide, and 250 ml of 7.2N aqueoushydrochloric acid in 400 ml of ethanol was refluxed for 3 hours. Themixture was cooled to 0° C. and the precipitate collected and washedtwice with hot ethyl acetate, three times with hot ethanol, and threetimes with ether. The product was dried under vacuum to afford 30.0 gm(38%) of compound (I-B),6-chloro-3,4-dihydro-3-[N-(ethoxycarbonylmethyl)aminomethyl]-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxidehydrochloride as a white solid: mp 209°-211° C. (dec).

To a mixture containing 12.31 gm (75.9 mmol) of3-acetylthio-2-methylpropionic acid in 10 ml of methylene chloride atroom temperature and under an atmosphere of nitrogen was added dropwiseover 35 minutes a solution of 12.25 gm (75.5 mmol) ofN,N'-carbonyldiimidazole in 100 ml of methylene chloride. After 30minutes a solution containing 16.96 gm (37.7 mmol) of6-chloro-3,4-dihydro-3-[N-(ethylcarbonylmethyl)aminomethyl]-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxidehydrochloride and 10.5 ml (75.3 mmol) of triethylamine in 10 ml ofmethylene chloride was added dropwise over a 20 minute period to thereaction mixture. After stirring at room temperature for 21 hours themixture was acidified by the addition of 30 ml of 9N ethanolic hydrogenchloride. The mixture was concentrated in vacuo and the residue washedtwice with ether. It was filtered through 175 gm of silica gel [23×4.3cm, acetone] to yield 6.7 gm (37%) of the crude product which could bechromatographed via HPLC [Water's 500, 5% ethanol in methylene chloride,k'=4.0] to yield compound (I-C),6-chloro-3,4-dihydro-3-[N-(ethoxycarbonylmethyl)-N-(3-acetylthio-2-methylpropanoyl)aminomethyl]-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxideas a white solid: mp 127°-130° C. ##STR8##

EXAMPLES II-VIII

The following compounds are made by analogous procedures familiar tothose of ordinary skill in this art:

    __________________________________________________________________________     ##STR9##                                                                     COMPOUND                                                                              A      Y R.sub.2                                                                              R.sub.4                                                                         Z.sub.1 M.sub.1                                     __________________________________________________________________________    II      CH.sub.3                                                                             H CH.sub.3                                                                             H CH.sub.2                                            III IV V                                                                              CH.sub.3 C.sub.6 H.sub.5 (CH.sub.3).sub.3 CCH.sub.2                                  H H H                                                                           CH.sub.3 CH.sub.3 (CH.sub.2).sub.4 NH.sub.2                                          H H H                                                                           CH(CH.sub.3) (CH.sub.2).sub.3 CH.sub.2                                                 ##STR10##                                  VI      C.sub.6 H.sub.5                                                                      H CH.sub.3                                                                             H (CH.sub.2).sub.2                                                                       ##STR11##                                  VII     CH.sub.3                                                                             H CH.sub.3                                                                             H (CH.sub.2).sub.2                                                                       ##STR12##                                  VIII    CH.sub.3                                                                             H CH.sub.3                                                                             H (CH.sub.2).sub.2                                                                       ##STR13##                                  __________________________________________________________________________

These compounds are:

II.6-Chloro-3,4-dihydro-3-[N-(carboxymethyl)-N-(3-acetylthio-2-methylpropanoyl)-aminomethyl]-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide.

III.6-Chloro-3,4-dihydro-3-[N-(carboxymethyl)-N-(3-acetylthio-2-methylpropanoyl)-1-aminoethyl]-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide.

IV.6-Chloro-3,4-dihydro-3-[N-(carboxymethyl)-N-(3-benzoylthio-2-methylpropanoyl)-3-aminopropyl]-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide.

V.6-Chloro-3,4-dihydro-3-[N-(carboxymethyl)-N-(2-(3,3,3-trimethylpropanoylthiomethyl-6-aminohexanoyl)aminomethyl]-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide.

VI.2,3-Dihydro-2-[N-(carboxymethyl)-N-(3-benzoylthio-2-methylpropanoyl)-2-aminoethyl]-6-sulfamoyl-5-chloro-1,2,3-benzothiadiazole-1,1-dioxide.

VII.7-Trifluoromethyl-1,2-dihydro-2-[N-(carboxymethyl)-N-(3-acetylthio-2-methylpropanoyl)-2-aminoethyl]-6-sulfamoyl-3H,4H-quinazoline-4-one.

VIII.1,2-Dihydro-2-[N-(carboxymethyl)-N-(3-acetylthio-2-methylpropanoyl)-2-aminoethyl]-5-sulfamoyl-6-chloro-3H-indazole-3-one.

What is claimed is:
 1. A compound of the formula ##STR14## or apharmaceutically acceptable salt thereof, wherein X is hydrogen or##STR15## wherein A is C₁₋₇ alkyl, phenyl, or phenyl substituted with upto 3 substituents selected from the group consisting of halo, C₁₋₇alkyl, --CF₃, --OH, --COOH, --NH₂, --SO₂ NH₂ ;m is 0 to 3 inclusive; Yis --OR or --N(R)R; R₁, R₂, R₃ and R₄ are independently R or amino-C₁₋₇alkyl; Z₁, reading toward the M₁ substituent, is selected from the groupconsisting of --(CH₂)_(n) --, --N(R)CH₂ (CH₂)_(n) --, --N(R)CH₂(CH₂)_(n) NH--, --(CH₂)_(n) SO₂ --, --(CH₂)_(n) N(R)SO₂ --, --(CH₂)_(n)--N(R)--, --(CH₂)_(n) N(R)C(O)--, --(CH₂)_(n) C(O)N(R)--, or --(CH₂)_(n)C(O)--, in which n is 0 to 6 inclusive, and one of the (CH₂) groups canbe mono- or disubstituted with methyl or ethyl; M₁ is benzothiadiazolehaving two or three substitutents selected from the group consisting ofhalogen, alkyl, aminoalkyl, aralkyl, cycloalkyl, alkylamino, acylamino,acylaminoalkyl, acylaminoalkylamino, trifluoromethyl, nitro, cyano,--OR, --SR, --C(O)OR, --S(O)R, --SO₂ R, --C(O)N(R)R, --N(R)R, or --SO₂N(R)R; wherein in each occurrence R is independently hydrogen, alkyl,cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaralkyl, or heteroaryl;wherein the alkyl groups and moieties have 1 to 7 carbon atoms, and thecycloalkyl, heteroalkyl, aryl and heteroaryl groups and moieties areselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, phenyl,tolyl, benzyl, phenethyl, indoyl, indolinyl, hydroxybenzyl, indanyl,naphthyl, tetrahydronaphthyl, decanhydronaphthyl, pyridyl, quinolyl,isoquinolyl, guanidino, pyrrolidyl, pyrrolyl, morpholinyl, furyl,furfuryl, tetrahydrofurfuryl, benzimidazolyl, thienyl, imidazolyl, andtetrahydroisoquinolyl.
 2. Compounds and salts according to claim 1wherein Y is hydroxy, lower alkoxy, --NH₂ or benzyloxy.
 3. Compounds andsalts according to claim 1 wherein R₁, R₂, R₃ and R₄ are independentlyhydrogen, lower alkyl, or amino-lower akyl.
 4. Compounds and saltsaccording to claim 2 wherein at least two of R₁, R₂, R₃ and R₄ arehydrogen.
 5. Compounds and salts according to claim 1 wherein Z₁ is--(CH₂)_(n) -- wherein n is 0 to
 6. 6. Compounds and salts according toclaim 1 whereinm is 1 to 3; Y is hydroxy, alkoxy having up to 4 carbonatoms, or benzyloxy; R₁ and R₃ are hydrogen; R₂ and R₄ are independentlyhydrogen or alkyl having up to 4 carbon atoms which is optionallysubstituted with amino; and Z₁ is --(CH₂)_(n) -- wherein n is 0 to
 6. 7.The compound according to claim 6 which is2,3-dihydro-2-[N-(Carboxymethyl)-N-(3-benzoylthio-2-methylpropanoyl)-2-aminoethyl]-6-sulfamoyl-5-chloro-1,2,3-benzothiadiazole-1,1-dioxide,and its pharmaceutically acceptable salts.
 8. A compound or saltaccording to claim 1 having one or more asymmetric centers each of whichis in the (S) configuration.
 9. A compound or salt according to claim 6having one or more asymmetric centers each of which is in the (S)configuration.
 10. A pharmaceutical preparation comprising a compound orsalt according to claim 1, in an amount effective to alleviatehypertension in a subject suffering therefrom, in association with apharmaceutically acceptable carrier.
 11. A method of treatinghypertension comprising administering to a subject suffering therefrom acompound or salt according to claim 1 in an amount effective toalleviate said hypertension.